Programa de Pós-graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Campus Capão do Leão, Pelotas, RS, CEP96010-900, Brazil.
Programa de Pós-Graduação em Química, Laboratório de Síntese Orgânica Limpa (LASOL), CCQFA, UFPel, Pelotas, RS, CEP 96010-900, Brazil.
Metab Brain Dis. 2021 Jun;36(5):871-888. doi: 10.1007/s11011-021-00703-w. Epub 2021 Mar 2.
Alzheimer's disease (AD) is a worldwide problem, and there are currently no treatments that can stop this disease. To investigate the binding affinity of 6-((4-fluorophenyl) selanyl)-9H-purine (FSP) with acetylcholinesterase (AChE), to verify the effects of FSP in an AD model in mice and to evaluate the toxicological potential of this compound in mice. The binding affinity of FSP with AChE was investigated by molecular docking analyses. The AD model was induced by streptozotocin (STZ) in Swiss mice after FSP treatment (1 mg/kg, intragastrically (i.g.)), 1st-10th day of the experimental protocol. Anxiety was evaluated in an elevated plus maze test, and memory impairment was evaluated in the Y-maze, object recognition and step-down inhibitory avoidance tasks. The cholinergic system was investigated based on by looking at expression and activity of AChE and expression of choline acetyltransferase (ChAT). We evaluated expression and activity of Na/K-ATPase. For toxicological analysis, animals received FSP (300 mg/kg, i.g.) and aspartate aminotransferase, alanine aminotransferase activities were determined in plasma and δ-aminolevulinate dehydratase activity in brain and liver. FSP interacts with residues of the AChE active site. FSP mitigated the induction of anxiety and memory impairment caused by STZ. FSP protected cholinergic system dysfunction and reduction of activity and expression of Na/K-ATPase. FSP did not modify toxicological parameters evaluated and did not cause the death of mice. FSP protected against anxiety, learning and memory impairment with involvement of the cholinergic system and Na/K-ATPase in these actions.
阿尔茨海默病（AD）是一个全球性的问题，目前尚无可以阻止这种疾病的治疗方法。为了研究 6-((4-氟苯基)硒基)-9H-嘌呤（FSP）与乙酰胆碱酯酶（AChE）的结合亲和力，验证 FSP 在 AD 模型中的作用，并评估该化合物在小鼠中的毒理学潜力。通过分子对接分析研究了 FSP 与 AChE 的结合亲和力。AD 模型通过 FSP 处理（1mg/kg，灌胃（i.g.））后用链脲佐菌素（STZ）在瑞士小鼠中诱导，实验方案的第 1-10 天。在高架十字迷宫测试中评估焦虑，在 Y 迷宫、物体识别和下抑制性回避任务中评估记忆障碍。根据 AChE 和胆碱乙酰转移酶（ChAT）的表达和活性研究胆碱能系统。我们评估了 Na/K-ATPase 的表达和活性。为了进行毒理学分析，动物接受 FSP（300mg/kg，i.g.）和天冬氨酸氨基转移酶、丙氨酸氨基转移酶活性在血浆中测定，δ-氨基酮戊酸脱水酶活性在大脑和肝脏中测定。FSP 与 AChE 活性位点的残基相互作用。FSP 减轻了 STZ 引起的焦虑和记忆障碍的诱导。FSP 保护胆碱能系统功能障碍，降低 Na/K-ATPase 的活性和表达。FSP 没有改变评估的毒理学参数，也没有导致小鼠死亡。FSP 通过涉及胆碱能系统和 Na/K-ATPase 的作用，预防焦虑、学习和记忆障碍。
